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BIG PHYSICS, BIG QUESTIONS –

The gene that closes the X files

By Claire O'brien

SURPLUS genes can be as disastrous for health as ones that are missing or mutated – think of Down’s syndrome, caused by an extra copy of chromosome 21. Every female embryo faces a similar threat. Both men and women need the genes carried on a single X chromosome, but women possess two, one of which must be silenced. In rare syndromes where this X inactivation is incomplete, women suffer from mental retardation and skeletal defects.

Neil Brockdorff and his team at the Medical Research Council’s Clinical Sciences Centre at the Royal Postgraduate Medical School in London have made an important breakthrough in understanding X inactivation by showing that a gene called Xist is essential to the process (Nature, vol 379, p 131). “This is the first direct evidence that the Xist gene is involved,” says Peter Goodfellow, a geneticist at the University of Cambridge, who studies sex chromosomes.

Very early in the development of female embryos, one randomly chosen X chromosome is silenced and condensed into a tightly packed form. Thereafter, only a tiny proportion of its genes remain active. Women suffering from incomplete X inactivation may lack part of the X chromosome that contains the human equivalent of the mouse gene studied by Brockdorff’s team – but the missing segment also contains other genes, so scientists had been unable to prove which gene is responsible.

Brockdorff’s team modified a line of cells taken from a mouse embryo. Each cell contained two X chromosomes with subtly different genetic sequences, so that they could be distinguished. One of the chromosomes also lacked about half of the Xist gene. The researchers inserted these cells into early mouse embryos at the 8-cell stage.

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Then they looked at what happened to the inserted cells’ X chromosomes some 10 days later. In all cases the copy containing the complete Xist gene was silenced. “The X chromosome with the deleted Xist gene never undergoes inactivation,” says Brockdorff.

The process of X inactivation involves a number of steps. A cell must count its X chromosomes and then “choose” which one to inactivate, before initiating the genetic program that shuts one chromosome down. How this counting and choice is achieved is still unclear. But Mary Lyon of the MRC’s Mammalian Genetics Unit in Didcot, Oxfordshire, who discovered X inactivation in 1961, notes that the chromosome counting step cannot be encoded by the portion of Xist deleted by Brockdorff’s team. Most of the cells still recognised that they needed to inactivate one chromosome, she points out.

One possibility is that different parts of the Xist gene control the counting, choice and shutdown functions. It should be possible to test this by examining the effects of deleting smaller fragments of Xist, says Hunt Willard of Case Western Reserve University in Cleveland, Ohio, whose team discovered the human version of the gene.